ABSTRACT: BIOENGINEERED PEPTIBODIES AS ANTIARRHYTHMIC THERAPY IN ATRIAL FIBRILLATION Atrial fibrillation (AF) is the most common arrhythmia seen in the clinic. It is particularly challenging to treat chronic AF and achieve restoration of sinus rhythm with currently available antiarrhythmics. This is in part due to the fact that current antiarrhythmic agents are inadequate, generally non- specific, and can carry risks of adverse effects. Therefore, there is an increasing need for novel, safe, and atrial specific antiarrhythmic therapies targeted for the treatment of chronic AF. In this R21 application, we propose to evaluate a peptibody which we bioengineered, and could be a potent blocker of the acetylcholine activated inward rectifier potassium current (IKACh). IKACh has been suggested to play an important role in chronic AF, making this potassium current a compelling therapeutic target. This bioengineered molecule was generated as a TertiapinQ- human IgG1 Fc fragment fusion protein. We will combine powerful concepts in protein engineering and cardiac electrophysiology in order to provide proof for the novel idea that anti-ion channels peptibodies can be potentially effective and specific antiarrhythmic modalities. We thus believe that our application is innovative and explores for the first time the idea that engineered anti-ion channels peptibodies could be a powerful therapeutic approach to a highly significant and increasingly prevalent cardiac electrophysiological disease.